The great Roman natural scientist Gaius Plinius Secundus (Pliny and Elder) in his comprehensive study, circa 60 AD, first described a most potent Indian Ocean sea hare of the genus Dolabella. (The Romans first designated Mollusca of the family Aplysidae as sea hares because of the similarity between the ears of a hare and the auriculate tentacles of these gastropods). However a consideration of the potential of the Indian Ocean Dolabella with respect to modern medical problems is only of recent origin. (See Pettit's U.S. Pat. Nos. 4,414,205, Nov. 8, 1983, Dolastatins 1-3; and 4,486,414, Dec. 4, 1984, Dolastatins A and B).
The dolastatins may correspond to the potent D. auricularia consituents (See: 1969 Ph. D. dissertation of M. Watson. U. of Hawaii, "Some Aspects of the Pharmacology, Chemistry and Biology of the Midgut Gland Toxins of Some Hawaiian Sea Hares, especially Dolabella auricularia and Aplysia pulmonica", University Microfilms, Inc., Ann Arbor, MI.)
The biological properties exhibited by the sea hare Dolabella auricularia have been pursued for centuries but it was only in 1972 that this laboratory found Indian Ocean specimens of this captivating sea hare which yielded extracts that proved effective (over 100% increase in life span) against the U.S. National Cancer Institute's (NCI) murine P388 lymphocytic leukemia (PS system). Subsequently, this laboratory succeeded in isolating nine new (and powerful) cell growth inhibitory and/or antineoplastic peptides which we designated dolastatins 1-9.
Of the early work, dolastatin 1 was found to be the most active (lowest dose) antineoplastic substance (33% cure rate against the NCI murine B16 melanoma at 11 .mu.g/kg) known in its time. Because of the dolastatin's potency, the sea hare seems to require only vanishingly small quantities (about 1 mg each fromm 100 kg), making isolation and structural elucidation of these peptides exceptionally challenging. The present disclosure is based on the isolation and structural determination of a unique linear pentapeptide herein denominated "dolastatin 10". This new substance may well be the most important Dolabella auricularia antineoplastic constituent located to date. Indeed, dolastatin 10 appears to be the most active (lowest dose) antineoplastic substance presently known, having shown a 17-67% curative response at 3.25-26 .mu.g/kg against the NCI human melanoma xenograph (nude mouse), 42-138% life extension at 1.44-11.1 .mu.g/kg using the B16 melanoma and 69-102% life extension at 1-4 .mu.g/kg against the PS leukemia (ED.sub.50 =4.6.times.10.sup.-5 .mu.g/ml).